[ Alan Leff ]

Alan Leff, M.D.

Primary:

Professor, Medicine

Secondary:

Departments of Anesthesia and Critical Care, Neurobiology
and Pediatrics

Committee on Cellular and Molecular Physiology
Committee on Clinical Pharmacology
Committee on Pharmacogenomics
Committee on Molecular Medicine
Education:
Degree Year Institution Area
AB
   1967
   Oberlin College 
   Dentistry (cum laude) Honors)
MD
   1971
   University of Rochester
  Medicine


Phone: (773) 702-1859
E-Mail: aleff@medicine.bsd.uchicago.edu
Address: AMB W663 (MC 6076)
Web page:
 http://med-www02.bsd.uchicago.edu/faculty_internet/faculty_profile.asp?empl_id=811

Research Summary

Immunopharmacology of inflammation: T cells and eosinophils

My research is conducted through the Airway Biology Research Group, which is a federally funded center for structured multidisciplinary collaboration of MD, and PhD investigators who are appointed in the Departments of Medicine and Pediatrics, and whose central interest is in the cellular pathophysiology of asthma and the maturational development of airway cells and tissues.

A major direction of this work is focused upon the inflammatory induction of airway hyperresponsiveness. These studies utilize ferromagnetically isolated peripheral human eosinophils and eosinophils cultured from pluripotential human umbilical cord blood to study the effects of cytokines, particularly IL-5 and GM-CSF and inflammatory mediators (especially platelet activating factor) on eosinophil function in guinea pig airway. Studies directed by Kimm Hamann, PhD have focused on the expression of eosinophil adhesion molecules and the adhesion and migration of these cells to cultured endothelial cells. Additional studies have focused upon epithelial activation and secretion and cell-cell communication of epithelium with underlying airway smooth muscle (Nilda Munoz, Senior Research Scientist). This work currently involves the characterization of the potential mediators of epithelial inhibition/secretion and utilizes two different primary cultures of epithelium. A further application of this work is the influence of inflammatory mediators, especially the major basic protein of eosinophils, on epithelial cell metabolism and the role of activated, isolated human eosinophils in transduction of epithelially mediated hyperresponsiveness in the guinea pig. 

A second area of investigation is the mechanism of signal transduction in eosinophils. Studies are being conducted to determine the relationship between molecular adhesion molecules and the upregulation of stimulated secretion from eosinophils during diapedesis and migration into bronchial airways.  These studies have lead to the observation that cytosolic PLA2 appears to be the essential messenger protein in all integrin adhesion (Xiangdong Zhu, MD).  Further studies are investigating the role of secretroy PLA2 in inflammatory cells.

Selected Publications

Kim, K.P., Rafter, J.D., Bittova, L., Han, S.K., Snitko, Y., Munoz, N.M., Leff, A.R. and Cho, W.  Mechanism of human group V phospholipase A2 (cPLA2)-induced leukotriene biosynthesis in human neutrophils. A potential role of heparan sulfate binding in PLA2 internalization and degradation. J. Biol. Chem., 276:11126-11134, 2001.

Myou, S., Sano, H., Fujimura, M., Zhu, X., Kurashima, K., Kita, T., Nakao, S., Nonomura, A., Kim, K.P., Shioya, T., Munoz, N.M., Cho, W. and Leff, A.R. Blockade of eosinophil migration and airway hypersponsiveness by cPLA2-inhibition. Nature Immunol., 2:145-149, 2001.

Sano, H., Zhu, X., Sano, A., Boetticher, E.E., Shioya, T., Munoz, N.M. and Leff, A.R. ERK1/2-mediated phosphorylation of cPLA2 is essential for human eosinophil adhesion to fibronectin. J. Immunol., 166:3515-3521, 2001.

Sano, A., Zhu, X., Sano, H., Munoz, N.M., Boetticher, E. and Leff, A.R.  Regulation of eosinophil function by phosphatidylinositol-specific PLC and cytosolic PLA2. Am. J. Physiol.: Lung Cell Mol. Physiol., 281:L844-L851, 2001.

Zhu, X., Jacobs, B., Boetticher, E., Myou, S., Melitan, A., Sano, H., Lambertino, A., Munoz, N. and Leff, A.R.   IL-5-induced integrin-adhesion of human eosinophils caused by ERK Â adctivation of cPLA2. J. Leukocyte Biol., in press, 2002.

Myou, S., Zhu, X., Boetticher, E., Myo, S., Meliton, A., Lambertino, A., Munoz, N.M. and Leff, A.R.  Blockade of focal clustering and active conformation of ß2-integrin-mediated adhesion of eosinophils to ICAM-1 caused by transduction of HIV TAT-dominant negative. Ras. J. Immunol., in press, 2002.

Updated 12/11/02.